Unexpected effects of terminal olefins on a cooperative recognition system that implicate olefin-olefin interactions

Full text of DOI:10.1002/anie.200901970

Angewandte
Chemie
DOI: 10.1002/anie.200901970
Olefin Detection
Unexpected Effects of Terminal Olefins on a Cooperative Recognition
System that Implicate Olefin–Olefin Interactions**
Rie Wakabayashi, Tomohiro Ikeda, Yohei Kubo, Seiji Shinkai,* and Masayuki Takeuchi*
To design receptors or building blocks that are useful for
constructing supramolecular architectures, multiple noncova-
lent, relatively weak interactions are essential to realize
flexible stimuli-responsive features. The systematic study of
such weak but crucial interactions is of great importance in
both synthetic and biological systems, but seem to be rather
difficult to estimate because of their weakness or lability to
the external environment. Among many approaches for
understanding such weak interactions, Wilcox and co-workers
introduced a smart method for the evaluation of CH–p
interactions using a “molecular torsion balance”, in which the
rotational barrier between folded (with interaction) and
unfolded (without interaction) states is used to calculate the
force.[1] Diederich and co-workers applied a chemical double-
mutant system[2] to the molecular torsion balance described
by Wilcox for the measurement of CF–amide interactions,
thus providing evidence that the stability is less than
4 kJmolÀ1.[3] In our recent study on the template synthesis
of a pseudorotaxane complex facilitated by allosterism,[4] we
noticed unexpectedly that the cooperative binding behavior
of a host molecule bearing olefin substituents at the periphery
of the binding sites are significantly different from those of a
non-olefinic counterpart. As the structures are basically the
same except for the presence or the absence of the terminal
olefins, this difference in cooperativity (see below) seems to
arise from the “interaction” among the olefin substituents.
Herein, we report the influence of the terminal olefin
substituents, which have been introduced into a series of
host molecules, on their allosteric behavior. Based on the
systematic investigation of the binding properties and the
structural analysis of the olefinic host molecules, we have
confirmed that the olefinic host molecules elicit a decrease in
cooperativity and an increase in affinity for the first guest
molecule. These findings clearly indicate that the weak
interactions that exist between the olefin substituents can be
detected using the allosteric recognition systems.
We first employed allosteric host molecules bearing four
zincporphyrin units as recognition sites (1a–1c) to demon-
strate the effect of terminal olefins on the recognition events
(Scheme 1).These molecules have been previously reported
to bind diamine molecules (4) with a 1:2 stoichiometry in an
allosteric manner.[4,5] The binding of the first diamine
molecule allows the recognition site for the second molecule
to be predisposed to binding another diamine molecule
because of the restriction of rotation around the butadiyne
axis; as a result, 1a–1c exhibit positive homotropic alloster-
ism toward 4 (Figure 1a).[6]
For the UV/Vis spectra of 1a, the bathochromic shifts in
the Q bands were observed upon successive addition of 4 in
CHCl3;[7] these changes arose from the formation of coordi-
nation bonds between zincporphyrins in 1 and amino groups
in 4. The degree of cooperativity can be analyzed by using the
Hill equation: log(y/1Ày) = nlog[guest] + log K, where the
values for n and K are the Hill coefficient and the association
constant, respectively.[8] It is known that a high n value results
from the increased cooperativity in a guest-binding process,
and the maximum n value is equal to the number of binding
sites of a host molecule. We previously reported that the
diamine binding to 1a has the Hill coefficient n = 1.9,[5,7] thus
indicating that two guest molecules are bound cooperatively.
The n values of 1b and 1c, bearing two and six pairs of
terminal olefins, respectively, were slightly smaller than that
of 1a; n = 1.8 for 1b and n = 1.6 for 1c.[4,7] Although the
observed difference in n values is relatively small, the
comparison of the first association constants (K1), which
was evaluated by a standard non-linear curve-fitting method,
reveals the significant difference among them; K1 = 1.6 ꢀ
105 mÀ1 for 1a, K1 = 4.7 ꢀ 105 mÀ1 for 1b, and K1 = 8.3 ꢀ
105 mÀ1 for 1c. Interestingly, the n and K1 values in the guest
recognition correlate with the number of terminal olefins in
the host molecules; that is, as the number of olefinic groups
increases, the n value decrease and the K1 value increase.
According to the Monod–Wyman–Changeux model for
positive homotropic allosterism, a degree of cooperativity
(the n value) closely correlates with the L value, where L is
defined as [T (an unbound conformation)]/[R (a bound
conformation)].[9] In this model, the higher L value results
in a higher n value, which supports the view that one can
qualitatively assume the conformation of a host molecule
without guest(s) from the n value.[10] Our finding, which shows
that the host molecules bearing terminal olefin substituents
[*] Dr. R. Wakabayashi, Dr. T. Ikeda, Dr. Y. Kubo, Prof. S. Shinkai
Department of Chemistry and Biochemistry
Graduate School of Engineering, Kyushu University
Fukuoka 819-0395 (Japan)
E-mail: seiji_center@mail.cstm.kyushu-u.ac.jp
Dr. M. Takeuchi
Macromolecules group, Organic Nanomaterials Center
National Institute for Materials Science
Tsukuba 305-0047 (Japan)
Fax: (+81)29-859-2101
http://www.nims.go.jp/macromol/
E-mail: takeuchi.masayuki@nims.go.jp
[**] M.T. thanks Dr. K. Sugiyasu (NIMS) for valuable comments. R.W.
thanks the JSPS Research Fellowship for Young Scientists for
financial support. This study was supported by KAKENHI
(19655051 and 19042018 to M.T) from the Ministry of Education,
Culture, Science, Sports, and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901970.
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a weak but significant interaction
operating between the peripheral ole-
fins; the interaction could influence
the initial conformation of the host
molecules and alter their allosteric
behavior.[11] To see if the changes
observed in their allosteric behavior
resulted from the initial conformation
of the host molecules we used 1d,
which was derived from 1b by a
metathesis reaction.[4] Since the rota-
tional movement around the central
axis is totally inhibited in 1d, the cleft
structure constructed between por-
phyrins is thoroughly predisposed for
4. The binding parameters of the 1d·42
complex were estimated to be n = 1.4
and K1 = 2.2 ꢀ 106 mÀ1 [7]
which led us
,
to conclude that 1d is an extreme case
of preorganization along the n order
of 1c < 1b < 1a for the recognition of
4. These findings support the view that
some weak interaction is operating
between the terminal olefins.
We further investigated host mol-
ecules bearing six zincporphyrins (2a
and 2b) and double-decker ceriu-
m(IV) bisporphyrinates (3a and 3b)
to amplify this weak interaction
(Scheme 2). It is already known that
2a forms 1:3 host–guest complexes
with 4[5] or C60,[12] and 3a forms 1:3
host–guest complexes with 5R[13] both
in an allosteric manner. The binding
parameters obtained from the UV/Vis
spectra and the circular dichroism
(CD) spectroscopic titrations are sum-
marized in Table 1.[14–17] For all cases,
we have confirmed that the terminal
olefins in host molecules show similar
trends in their guest-binding parame-
ters, even when we used different
host–guest combinations and condi-
tions. Comparison of the Hill param-
eters for 2b with 2a reveals that the
preorganization tendency (i.e., the
decrease in n and the increase in
K1 values) is further intensified by
the “interaction” of nine pairs of
terminal olefins.[18]
Scheme 1. Allosteric hosts 1a–d and guest molecule 4.
Figure 1. Schematic representation of the binding behavior of the guest molecule with the
allosteric host molecule a) without olefinic groups and b) with olefinic groups. The R state
represents the guest-bound conformation and the T state represents the guest-unbound
conformation.
Finally, 1H NMR measurements
were acquired to obtain spectroscopic
evidence for the difference in the
1
give the lower cooperativity (smaller n value), indicates that
the initial conformation of the unbound olefinic host mole-
cules is more or less inclined toward the guest-complexed
conformation (R state). In such a conformation, the periph-
eral olefin substituents must exist in close proximity to each
other (Figure 1b). We infer that this phenomenon is caused by
initial conformation of the host molecules. In the H NMR
spectra of 1a–c in CDCl3, little difference was observed
among them at both 298 K and 253 K (see the Supporting
Information). This outcome indicates that the difference in
the conformation is negligibly small (if any), and it is difficult
to detect by means of the 1H NMR spectroscopy. In contrast,
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more defined conformation, which
would arise from the interaction
between the terminal olefins.
As shown here, the weak but
significant influence of the termi-
nal olefins at the periphery of
binding sites exists, and is detect-
able as characteristic parameters
for the allosteric recognition pro-
cesses; that is, the decrease in
cooperativity and the increase in
affinity. Moreover, the phenom-
ena we have demonstrated here
are not affected by the difference
in the structures of both host and
guest species. These results consis-
tently imply the presence of a
weak interaction between the ter-
minal olefin substituents. In other
words, this approach may be con-
sidered to be a new method to
demonstrate the weak attractive
forces operating in, for example,
p–p, CH–p, and cation–p interac-
tions. There are three key points in
the present system: 1) a periaxial
Scheme 2. Allosteric hosts 2 and 3 and guest molecules.
rotation, which does not change
the molecular structure signifi-
cantly, is used to induce a confor-
Table 1: Selected binding parameters of the guest recognition by
porphyrinatozinc tetramers 1a–d, hexamers 2a and 2b, and double-
decker porphyrin complexes 3a and 3b.[14]
mational change; 2) the allosteric system used here is
sensitive enough to be readily influenced by the external or
internal environment; 3) combination with the host–guest
system provides an advantage to make the stimulus trans-
duction process clear. Our new approach, which incorporates
the weak interaction in synthetic allosteric receptors, will
become a complementary tool for the detection or the
confirmation of weak interactions. Also possible is the
structural control of the higher-order architectures using
terminal olefins, not only in artificial systems but also in
biological systems.
Host Guest Number
of olefins
n
K1 10À5 [mÀ1 log Ktot DG [kJmolÀ1
] ]
1a
1b
1c
1d
2a
2b
2a
2b
3a
3b
4
4
4
4
4
4
C60
C60
5R
5R
0
1.9 1.6
10.69
11.23
11.83
12.30
18.59
18.91
8.15
8.43
8.35
8.73
À60.96
À64.08
À67.48
À70.11
À106.06
À107.88
À46.47
À48.12
À47.64
À49.81
4 (2 pairs) 1.8 4.7
12 (6 pairs) 1.6 8.3
–
0
1.4 22
2.8 8.8
18 (9 pairs) 1.8 15
[a]
0
2.8 –
18 (9 pairs) 1.6 5.6ꢀ10À3
[a]
Received: April 13, 2009
Revised: July 1, 2009
Published online: July 31, 2009
0
3.0
–
2 (1 pair)
1.8 7.7ꢀ10À3
[a] The binding process is highly cooperative.
Keywords: allosterism · molecular recognition ·
.
noncovalent interactions · olefins · porphyrinoids
two porphyrin planes in double-decker cerium(IV) bispor-
phyrinates feature the relatively slow rotation rate around the
central cerium ion, and the rotation is slow enough to be
followed by variable temperature NMR analysis.[19] The
exchange between rotational isomers is often estimated by
monitoring the chemical shifts of the b-pyrrole protons.[19] The
1H NMR spectra of 3a and 3b at 233 K gave complicated
patterns in the b-pyrrole region (8.36–8.51 ppm), however,
one can recognize the difference between 3a and 3b (see the
Supporting Information). The spectrum of 3b is somewhat
simpler than that of 3a, and similar to the pattern of A3B-type
porphyrins. These results suggest that 3b tends to adopt the
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Communications
[5] Y. Kubo, Y. Kitada, R. Wakabayashi, T. Kishida, M. Ayabe, K.
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[7] See the Supporting Information for details of UV/Vis spectro-
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[14] The cooperative guest-binding process was analyzed according
to the Hill equation and a nonlinear least-squares method. The
Ktot values were obtained by the multiplication of each sequen-
tial binding constant or by the Hill equation for 2a with C60 and
3a with 5R, which showed the maximum cooperativity. The
Gibbs free energy change (DG) was calculated by the equation:
DG = ÀRTlnKtot, where R and T are the gas constant and
temperature, respectively.
[15] See the Supporting Information for details of UV/Vis spectro-
scopic titration of 2a–2b with 4 in CHCl3 (Figures S6–S8).
[16] See the Supporting Information for details of UV/Vis spectro-
scopic titration of 2b with C60 in toluene (Figures S9 and S10).
[17] See the Supporting Information for details of circular dichroism
spectroscopic titration of 3a–3b with 5R in CH2Cl2/AcOEt =
30:1 (v/v; Figures S11–S13).
[18] Host molecules 1a–c show the higher effects on the energy
difference in DG between olefinic and non-olefinic hosts
compared to those of 2. This energy difference probably arises
from the shorter distance between olefin substituents within 1b
and 1c, and/or to the less rotational freedom of 1 than that of 2;
host molecules 1 have only one rotational axis within the
structure whereas the receptors 2 have as many as three axes.
[19] M. Takeuchi, T. Imada, M. Ikeda, S. Shinkai, Tetrahedron Lett.
1998, 39, 7897 – 7900.
[10] We recently demonstrated that an unconventional enantioselec-
tive recognition system for 5R can be designed using an
allosteric double-decker host molecule. Since the allosteric
host is predisposed for memorized 5R (R state) but it is
sterically biased for the unmemorized S enantiomer (T state),
the host molecule can differentiate between two enantiomers
with extremely high selectivity; that is, the host molecule binds
the R enantiomer (n = 1.6 and K1 = 1.3 ꢀ 103 mÀ1
) with low
cooperativity whereas it binds the S enantiomer (n = 2.9 and
K1 = 5.0mÀ1) with high cooperativity. This result implies that the
original conformation of a host molecule exerts a strong effect
on the cooperativity in the binding of guest molecules, see: T.
Ikeda, O. Hirata, M. Takeuchi, S. Shinkai, J. Am. Chem. Soc.
2006, 128, 16008 – 16009.
[11] At this stage, it is unclear for us whether this weak interaction
arises from p–p, CH–p, or van der Waals interaction, or the
cooperative interaction between them. In addition, we cannot
rule out the influence of the difference in the alkyl chain lengths
between olefinic and non-olefinic receptors. It is more likely,
however, that “olefinic substituents”, which include the differ-
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